Abstract 911: Cancer stem cells establish intrinsic immune resistance through suppressing IFN-mediated antitumor immunity

Abstract Although the cancer immunotherapy has generated promising outcomes in the clinics, a substantial proportion of cancer patients either show resistance to immunotherapy or experience relapse following an initial response. This issue is particularly urgent for patients with squamous cell carcinomas (SCCs), highlighting the critical need to understand the mechanisms behind immune evasion and immunotherapy resistance in these cancers. Recently, our lab identified a subset of tumor-initiating stem cells (tSCs) in skin and head/neck SCCs that respond to transforming growth factor β (TGF-β) and play a key role in driving tumor relapse post-immunotherapy. Notably, these tSCs are resistant to T-cell attacks despite retaining functional antigen presentation, resulting in only transient responses to immune checkpoint blockade therapy across SCC types. Here, my current study has uncovered a central role for Sox2 as a master regulator that drives immune resistance in TGF-β-responsive tSCs. Through RNA-seq and qPCR analyses, we observed that Sox2 amplification in tSCs significantly blunted their interferon-γ (IFN-γ) responsive potentials. Mechanistically, we found that Sox2 neither blocks IFN-γ signaling transduction nor directly binds to the enhancers or promoters of most IFN-γ-induced genes. Instead, we discovered that the reduced IFN-γ response in Sox2-overexpressing cells is likely due to the altered Stat1-mediated transcriptional repression. This study uncovered a stem cell specific transcription regulation that provides new insights in developing new strategies to abolish tSC-specific immune resistance. Citation Format: Xuejie Huang, Weijie Guo, Yuxuan Phoenix Miao. Cancer stem cells establish intrinsic immune resistance through suppressing IFN-mediated antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 911.